Phenoxy-azetidine derivatives as sphingosine 1-phosphate (s1p) receptor modulators

ABSTRACT

The present invention relates to novel phenoxy-azetidine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 61/601,084, filed Feb. 21, 2012, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to phenoxy-azetidine derivatives,processes for preparing them, pharmaceutical compositions containingthem and their use as pharmaceuticals, as modulators of thesphingosine-1-phosphate receptors. The invention relates specifically tothe use of these compounds and their pharmaceutical compositions totreat disorders associated with sphingosine-1-phosphate (S1P) receptormodulation.

BACKGROUND OF THE INVENTION

Sphingosine-1 phosphate is stored in relatively high concentrations inhuman platelets, which lack the enzymes responsible for its catabolism,and it is released into the blood stream upon activation ofphysiological stimuli, such as growth factors, cytokines, and receptoragonists and antigens. It may also have a critical role in plateletaggregation and thrombosis and could aggravate cardiovascular diseases.On the other hand the relatively high concentration of the metabolite inhigh-density lipoproteins (HDL) may have beneficial implications foratherogenesis. For example, there are recent suggestions thatsphingosine-1-phosphate, together with other lysolipids such assphingosylphosphorylcholine and lysosulfatide, are responsible for thebeneficial clinical effects of HDL by stimulating the production of thepotent antiatherogenic signaling molecule nitric oxide by the vascularendothelium. In addition, like lysophosphatidic acid, it is a marker forcertain types of cancer, and there is evidence that its role in celldivision or proliferation may have an influence on the development ofcancers. These are currently topics that are attracting great interestamongst medical researchers, and the potential for therapeuticintervention in sphingosine-1-phosphate metabolism is under activeinvestigation.

SUMMARY OF THE INVENTION

A group of novel phenoxy-azetidine derivatives, which are potent andselective sphingosine-1-phosphate modulators has been discovered. Assuch, the compounds described herein are useful in treating a widevariety of disorders associated with modulation of thesphingosine-1-phosphate receptors. The term “modulator” as used herein,includes but is not limited to: receptor agonist, antagonist, inverseagonist, inverse antagonist, partial agonist, partial antagonist.

This invention describes compounds of Formula I, which havesphingosine-1-phosphate receptor biological activity. The compounds inaccordance with the present invention are thus of use in medicine, forexample in the treatment of humans with diseases and conditions that arealleviated by S1P modulation.

In one aspect, the invention provides a compound represented by FormulaI or a pharmaceutically acceptable salt thereof or stereoisomeric formsthereof, or the geometrical isomers, enantiomers, diastereoisomers,tautomers, zwitterions and pharmaceutically acceptable salts thereof

wherein:

-   A is optionally substituted C₆₋₁₀ aryl, optionally substituted    heterocycle, optionally substituted C₃₋₈ cycloalkyl or optionally    substituted C₃₋₈ cycloalkenyl;-   B is optionally substituted C₆₋₁₀ aryl, optionally substituted    heterocycle, optionally substituted C₃₋₈ cycloalkyl or optionally    substituted C₃₋₈ cycloalkenyl;-   R¹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R² is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R³ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁴ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁵ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁶ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁷ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁸ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R¹⁰ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, C₆₋₁₀ aryl, optionally substituted heterocycle,    optionally substituted C₃₋₈ cycloakyl, optionally substituted C₃₋₈    cycloalkenyl, NR¹²R¹³ or hydroxyl;-   L¹ is O, S, NH or CHR¹²;-   L² is O, S or CHR¹²;-   R¹¹ is H, OH or C₁₋₈ alkyl;-   a is 1, 2, 3, 4, 5 or 6;-   R¹² is H or C₁₋₈ alkyl; and-   R¹³ is H or C₁₋₈ alkyl.    In another aspect, the invention provides a compound represented by    Formula I wherein:-   A is optionally substituted C₆₋₁₀ aryl, optionally substituted    heterocycle, C₃₋₈ cycloalkyl or optionally substituted C₃₋₈    cycloalkenyl;-   B is optionally substituted C₆₋₁₀ aryl, optionally substituted    heterocycle, optionally substituted C₃₋₈ cycloalkyl or optionally    substituted C₃₋₈ cycloalkenyl;-   R¹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R² is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R³ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁴ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁵ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁶ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁷ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁸ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R¹⁰ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   L¹ is CH₂;-   L² is O, S or CHR¹²;-   R¹¹ is H, OH or C₁₋₈ alkyl;-   a is 1, 2, 3, 4, 5 or 6;-   R¹² is H or C₁₋₈ alkyl;-   R¹³ is H or C₁₋₈ alkyl.    In another aspect, the invention provides a compound represented by    Formula I wherein:-   A is optionally substituted C₆₋₁₀ aryl, optionally substituted    heterocycle, C₃₋₈ cycloalkyl or optionally substituted C₃₋₈    cycloalkenyl;-   B is optionally substituted C₆₋₁₀ aryl, optionally substituted    heterocycle, optionally substituted C₃₋₈ cycloalkyl or optionally    substituted C₃₋₈ cycloalkenyl;-   R¹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R² is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R³ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁴ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁵ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁶ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁷ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁸ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R¹⁰ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   L¹ is CH₂;-   L² is CH₂;-   R¹¹ is H, OH or C₁₋₈ alkyl;-   a is 1, 2, 3, 4, 5 or 6;-   R¹² is H or C₁₋₈ alkyl;-   R¹³ is H or C₁₋₈ alkyl.    In another aspect, the invention provides a compound represented by    Formula I wherein:-   A is optionally substituted C₆₋₁₀ aryl, optionally substituted    heterocycle, C₃₋₈ cycloalkyl or optionally substituted C₃₋₈    cycloalkenyl;-   B is optionally substituted C₆₋₁₀ aryl, optionally substituted    heterocycle, optionally substituted C₃₋₈ cycloalkyl or optionally    substituted C₃₋₈ cycloalkenyl;-   R¹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R² is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R³ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁴ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁵ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁶ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁷ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁸ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R¹⁰ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   L¹ is O, S, NH or CHR¹²;-   L² is O, S or CHR¹²;-   R¹¹ is H, OH or C₁₋₈ alkyl;-   a is 1, 2 or 3;-   R¹² is H or C₁₋₈ alkyl;-   R¹³ is H or C₁₋₈ alkyl.    In another aspect, the invention provides a compound represented by    Formula I wherein:

-   R¹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R² is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R³ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁴ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁵ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁶ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁷ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁸ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R¹⁰ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   L¹ is O, S, NH or CH R¹²;-   L² is O, S or CHR¹²;-   R¹¹ is H, OH or C₁₋₈ alkyl;-   a is 1, 2 or 3;-   R¹² is H or C₁₋₈ alkyl;-   R¹³ is H or C₁₋₈ alkyl.    In another aspect, the invention provides a compound represented by    Formula I wherein:

-   R¹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R² is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R³ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁴ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁵ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁶ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁷ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁸ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R¹⁰ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   L¹ is O, S, NH or CH R¹²;-   L² is O, S or CHR¹²;-   R¹¹ is H, OH or C₁₋₈ alkyl;-   a is 1, 2 or 3;-   R¹² is H or C₁₋₈ alkyl;-   R¹³ is H or C₁₋₈ alkyl.    In another aspect, the invention provides a compound represented by    Formula I wherein

-   R¹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R² is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R³ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁴ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁵ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁶ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁷ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁸ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R¹⁰ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   L¹ is O, S, NH or CH R¹²;-   L² is O, S or CHR¹²;-   R¹¹ is H, OH or C₁₋₈ alkyl;-   a is 1, 2 or 3;-   R¹² is H or C₁₋₈ alkyl;-   R¹³ is H or C₁₋₈ alkyl.    In another aspect, the invention provides a compound represented by    Formula I wherein

-   R¹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R² is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R³ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁴ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁵ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁶ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl;-   R⁷ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁸ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R¹⁰ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   L¹ is O, S, NH or CH R¹²;-   L² is O, S or CHR¹²;-   R¹¹ is H, OH or C₁₋₈ alkyl;-   a is 1, 2 or 3;-   R¹² is H or C₁₋₈ alkyl;-   R¹³ is H or C₁₋₈ alkyl.    In another aspect, the invention provides a compound represented by    Formula I wherein wherein:

R¹ is H or halogen;

R² is H or halogen;

R³ is H or halogen;

R⁴ is H or halogen;

R⁵ is H or C₁₋₈ alkyl;

R⁶ is H or C₁₋₈ alkyl;

-   R⁷ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁸ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R⁹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   R¹⁰ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl,    CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionally    substituted heterocycle, optionally substituted C₃₋₈ cycloakyl,    optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;-   L¹ is O, S, NH or CH₂;-   L² is O, S or CH₂,-   R¹¹ is H, OH or C₁₋₈ alkyl;-   a is 1, 2, 3, 4, 5 or 6;-   R¹² is H or C₁₋₈ alkyl;-   R¹³ is H or C₁₋₈ alkyl.

The term “alkyl”, as used herein, refers to saturated, monovalenthydrocarbon moieties having linear or branched moieties or combinationsthereof and containing 1 to 8 carbon atoms. One methylene (—CH₂—) group,of the alkyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, or by a divalent C₃₋₈ cycloalkyl. Alkylgroups can be independently substituted by halogen atoms, hydroxylgroups, cycloalkyl groups, amine groups, heterocyclic groups, carboxylicacid groups, phosphonic acid groups, sulphonic acid groups, phosphoricacid groups, nitro groups, amide groups, sulfonamides groups.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be independently substituted by halogen, nitro groups,cyano groups, —OC₁₋₆ alkyl groups, —SC₁₋₆alkyl groups, —C₁₋₆ alkylgroups, —C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, C₃₋₈ cycloalkylgroups, carboxylic acid groups, ester groups, ketone groups, aldehydegroups, amide groups, amine groups, sulfonamide groups or hydroxylgroups.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturatedcycloalkyl having one double bond. Cycloalkenyl groups can be monocyclicor polycyclic. Cycloalkenyl groups can be independently substituted byhalogen atoms, nitro groups, cyano groups, —OC₁₋₆ alkyl groups,—SC₁₋₆alkyl groups, —C₁₋₆ alkyl groups, —C₂₋₆ alkenyl groups, —C₂₋₆alkynyl groups, carboxylic acid groups, ester groups, ketone groups,aldehyde groups, amide groups, amine groups, sulfonamide groups, C₃₋₈cycloalkyl groups or hydroxyl groups.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. C₂₋₆ alkenyl can be in the E orZ configuration. Alkenyl groups can be substituted by C₁₋₈ alkyl.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or non-saturated,monocyclic or polycyclic, containing at least one heteroatom selectedform O or N or S or combinations of at least two thereof, interruptingthe carbocyclic ring structure. The heterocyclic ring can be interruptedby a C═O; the S heteroatom can be oxidized. Heterocycles can bemonocyclic or polycyclic. Heterocyclic ring moieties can be substitutedby halogen, nitro groups, cyano groups, —OC₁₋₆ alkyl groups, —SC₁₋₆alkylgroups, —C₁₋₆ alkyl groups, —C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups,carboxylic acid groups, ester groups, ketone groups, aldehyde groups,amide groups, amine groups, sulfonamide groups, C₃₋₈ cycloalkyl groupsor hydroxyl groups.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms by removal of one hydrogen. Aryl can be monocyclic or polycyclic.Aryl can be substituted by halogen atoms, nitro groups, cyano groups,—OC₁₋₆ alkyl groups, —SC₁₋₆alkyl groups, —C₁₋₆ alkyl groups, —C₂₋₆alkenyl groups, —C₂₋₆ alkynyl groups , carboxylic acid groups, estergroups, ketone groups, aldehyde groups, amide groups, amine groups,sulfonamide groups, C₃₋₈ cycloalkyl groups or hydroxyl groups. Usuallyaryl is phenyl. Preferred substitution site on aryl are meta and parapositions.

The term “cyano” as used herein, represents a group of formula “—CN”.

The term “nitro” as used herein, represents a group of formula “—NO₂”.

The term “amide” as used herein, represents a group of formula“—C(O)NR^(x)R^(y),” wherein R^(x) and R^(y) can be the same orindependently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyle asdefined above.

The term “amine” as used herein, represents a group of formula“—NR^(x)R^(y)”,wherein R^(x) and R^(y) can be the same or independentlyH, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyle as defined above.

The term “ketone” as used herein, represents an organic compound havinga carbonyl group linked to a carbon atom such as —(CO)R^(x) whereinR^(x) can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyle asdefined above.

The term “aldehyde” as used herein, represents a group of formula“—C(O)H”.

The term “ester” as used herein, represents a group of formula“—C(O)OR^(x)”, wherein R^(x) can be alkyl, aryl, cycloalkyl,cycloalkenyl, heterocyle as defined above.

The term “sulfonamide” as used herein, represents a group of formula“—S(O)₂NR^(x)R^(y)” wherein R^(x) and R^(y) can be the same orindependently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyle asdefined above.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)”.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula“—SO₂”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “sulfoxide” as used herein, represents a group of formula“—S═O”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—(O)P(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

Compounds of the invention are:

-   1-{4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}azetidine-3-carboxylic    acid;-   1-(4-[4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)azetidine-3-carboxylic    acid;-   1-(4-{[4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)azetidine-3-carboxylic    acid;-   1-(4-{[5-(3-chlorophenyl)-6-(3,4-dimethylphenyl)hexyl]oxy}benzyl)azetidine-3-carboxylic    acid;-   b    1-(4-{[4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)pentyl]sulfinyl}benzyl)azetidine-3-carboxylic    acid;-   1-(4-{[4-(2,3-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)azetidine-3-carboxylic    acid;-   1-(4-{[4-(3,4-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)azetidine-3-carboxylic    acid;-   1-(4-{[5-(3,4-dimethylphenyl)-4-(3-thienyl)pentyl]oxy}benzyl)azetidine-3-carboxylic    acid.

Some compounds of Formula I and some of their intermediates have atleast one stereogenic center in their structure. This stereogenic centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appli. Chem. (1976),45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid andthe like; or an organic acid such as for example, acetic acid,hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonicacid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinicacid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid,citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonicacid, formic and the like (Handbook of Pharmaceutical Salts, P. HeinrichStahal & Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta-Zürich,2002, 329-345).

The base addition salt form of a compound of Formula I that occurs inits acid form can be obtained by treating the acid with an appropriatebase such as an inorganic base, for example, sodium hydroxide, magnesiumhydroxide, potassium hydroxide, Calcium hydroxide, ammonia and the like;or an organic base such as for example, L-Arginine, ethanolamine,betaine, benzathine, morpholine and the like. (Handbook ofPharmaceutical Salts, P. Heinrich Stahal & Camille G. Wermuth (Eds),Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).

Compounds of Formula I and their salts can be in the form of a solvate,which is included within the scope of the present invention. Suchsolvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The compounds of the invention are indicated for use in treating orpreventing conditions in which there is likely to be a componentinvolving the sphingosine-1-phosphate receptors.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of sphingosine-1-phosphatereceptors. Such methods can be performed, for example, by administeringto a subject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated byS1P modulation.

Therapeutic utilities of S1P modulators are ocular diseases, such as butnot limited to:

-   -   Ocular Diseases: wet and dry age-related macular degeneration,        diabetic retinopathy, retinopathy of prematurity, retinal edema,        dry eye, geographic atrophy, glaucomatous optic neuropathy,        chorioretinopathy, hypertensive retinopathy, ocular ischemic        syndrome, prevention of inflammation-induced fibrosis in the        back of the eye, various ocular inflammatory diseases including        uveitis, scleritis, keratitis, and retinal vasculitis;    -   Systemic vascular barrier related diseases: various inflammatory        diseases, including acute lung injury, its prevention, sepsis,        tumor metastasis, atherosclerosis, pulmonary edemas, and        ventilation-induced lung injury;    -   Autoimmune diseases and immnuosuppression: rheumatoid arthritis,        Crohn's disease, Graves' disease, inflammatory bowel disease,        multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative        colitis, antoimmune uveitis, renal ischemia/perfusion injury,        contact hypersensitivity, atopic dermititis, and organ        transplantation;    -   Allergies and other inflammatory diseases: urticaria, bronchial        asthma, and other airway inflammations including pulmonary        emphysema and chronic obstructive pulmonary diseases;    -   Cardiac functions: bradycardia, congestional heart failure,        cardiac arrhythmia, prevention and treatment of atherosclerosis,        and ischemia/reperfusion injury;    -   Wound Healing: scar-free healing of wounds from cosmetic skin        surgery, ocular surgery, GI surgery, general surgery, oral        injuries, various mechanical, heat and burn injuries, prevention        and treatment of photoaging and skin ageing, and prevention of        radiation-induced injuries;

-   Bone formation: treatment of osteoporosis and various bone fractures    including hip and ankles;    -   Anti-nociceptive activity: visceral pain, pain associated with        diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, neuropathic pains;    -   Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis,        proliferative vitreoretinopathy, cicatricial pemphigoid,        surgically induced fibrosis in cornea, conjunctiva and tenon;    -   Pains and anti-inflammation: acute pain, flare-up of chronic        pain, musculo-skeletal pains, visceral pain, pain associated        with diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, bursitis, neuropathic        pains;    -   CNS neuronal injuries: Alzheimer's disease, age-related neuronal        injuries;    -   Organ transplants: renal, corneal, cardiac and adipose tissue        transplants.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation ofsphingosine-1-phosphate receptors. Such methods can be performed, forexample, by administering to a subject in need thereof a therapeuticallyeffective amount of at least one compound of the invention, or anycombination thereof, or pharmaceutically acceptable salts, hydrates,solvates, crystal forms and individual isomers, enantiomers, anddiastereomers thereof.

The present invention concerns the use of a compound of Formula I or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of

Ocular Diseases: wet and dry age-related macular degeneration, diabeticretinopathy, retinopathy of prematurity, retinal edema, dry eye,geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy,hypertensive retinopathy, ocular ischemic syndrome, prevention ofinflammation-induced fibrosis in the back of the eye, various ocularinflammatory diseases including uveitis, scleritis, keratitis, andretinal vasculitis;

Systemic vascular barrier related diseases: various inflammatorydiseases, including acute lung injury, its prevention, sepsis, tumormetastasis, atherosclerosis, pulmonary edemas, and ventilation-inducedlung injury;

Autoimmune diseases and immnuosuppression: rheumatoid arthritis, Crohn'sdisease, Graves' disease, inflammatory bowel disease, multiplesclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, antoimmuneuveitis, renal ischemia/perfusion injury, contact hypersensitivity,atopic dermititis, and organ transplantation;

Allergies and other inflammatory diseases: urticaria, bronchial asthma,and other airway inflammations including pulmonary emphysema and chronicobstructive pulmonary diseases;

Cardiac functions: bradycardia, congestional heart failure, cardiacarrhythmia, prevention and treatment of atherosclerosis, andischemia/reperfusion injury;

Wound Healing: scar-free healing of wounds from cosmetic skin surgery,ocular surgery, GI surgery, general surgery, oral injuries, variousmechanical, heat and burn injuries, prevention and treatment ofphotoaging and skin ageing, and prevention of radiation-inducedinjuries;

Bone formation: treatment of osteoporosis and various bone fracturesincluding hip and ankles;

Anti-nociceptive activity: visceral pain, pain associated with diabeticneuropathy, rheumatoid arthritis, chronic knee and joint pain,tendonitis, osteoarthritis, neuropathic pains;

Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis,proliferative vitreoretinopathy, cicatricial pemphigoid, surgicallyinduced fibrosis in cornea, conjunctiva and tenon;

Pains and anti-inflammation: acute pain, flare-up of chronic pain,musculo-skeletal pains, visceral pain, pain associated with diabeticneuropathy, rheumatoid arthritis, chronic knee and joint pain,tendonitis, osteoarthritis, bursitis, neuropathic pains;

CNS neuronal injuries: Alzheimer's disease, age-related neuronalinjuries;

Organ transplants: renal, corneal, cardiac and adipose tissuetransplants.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Invention compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists ofsphingosine-1-phosphate receptors. Thus, in further embodiments of theinvention, there are provided methods for treating a disorder associatedwith modulation of sphingosine-1-phosphate receptors. Such methods canbe performed, for example, by administering to a subject in need thereofa pharmaceutical composition containing a therapeutically effectiveamount of at least one invention compound. As used herein, the term“therapeutically effective amount” means the amount of thepharmaceutical composition that will elicit the biological or medicalresponse of a subject in need thereof that is being sought by theresearcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry. The synthetic schemes set forth below, illustrate howcompounds according to the invention can be made.

Those skilled in the art will be able to routinely modify and/or adaptthe following scheme to synthesize any compounds of the inventioncovered by Formula I.

The following abbreviations are used in the general scheme descriptionand in the examples:

-   AcCN acetonitrile-   DCM dichloromethane-   MeOH methanol-   CD₃OD deuterated methanol-   CDCl₃ deuterated chloroform-   DMSO-d₆ deuterated dimethyl sulfoxide-   TEA triethylamine-   RT or rt room temperature-   M molar-   AcOH acetic acid-   MPLC Medium Pressure Liquid Chromatography-   NMO 4-Methylmorpholine N-oxide-   TPAP Tetrapropylammonium perruthenate-   NaBH₄ Sodium borohydride-   NaCNBH₃ Sodium cyanoborohydride

General Procedure A

The alcohol intermediate (0.61 mmol) was mixed with NMO (15.4 mmol),molecular sieve (500 mg) in AcCN (6 mL) and DCM (30 mL). A catalyticamount of TPAP (35 mg) was added. The resulting reaction mixture wasstirred at RT for 1 hour and evaporated to dryness. The aldehydecompound was purified by MPLC using 0-10% ethyl acetate in hexane.

General Procedure B

The aldehyde (0.68 mmol), azetidine acid (0.88 mmol) and TEA (0.7 mmol)were mixed with MeOH (10 m1). Upon stirring at 60° C. for 90 min, thereaction solution was cooled to RT. NaBH₄ (50 mg) was added and stirredat RT for 2 hour. The reaction was quenched with 0.5 mL of water andconcentrated to minimal amount. The titled compound was isolated byreverse phase MPLC using 0 to 90% H₂O in AcCN.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of protium ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACD version 12.0 and intermediatesand reagent names used in the examples were generated with software suchas Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw2.5 SP1.

In general, characterization of the compounds is performed according tothe following methods:

-   NMR spectra are recorded on 300 and/or 600 MHz Varian and acquired    at room temperature; or at 60 MHz on a Varian T-60 spectrometer or    at 300 MHz on a Varian Inova system.-   Chemical shifts are given in ppm referenced either to internal TMS    or to the solvent signal. All the reagents, solvents, catalysts for    which the synthesis is not described are purchased from chemical    vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI,    VWR, Lancaster, Oakwood, Trans World Chemical, Alfa,    AscentScientific LLC., Fisher, Maybridge, Frontier, Matrix,    Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem,    Chem-Impex, MIC-scientific, Ltd; however some known intermediates,    were prepared according to published procedures. Column    chromatography (Auto-column) on a Teledyne-ISCO CombiFlash with a    silica column, unless noted otherwise.

Those skilled in the art will be routinely able to modify and/or adaptthe following procedures to synthesize any compound of the inventioncovered Formula I.

EXAMPLE 1 Intermediate 14-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzaldehyde

The corresponding alcohol intermediate (2.43 g, 0.61 mmol) was mixedwith NMO (1.79 g, 15.4 mmol) , molecular sieve (500 mg) in AcCN (6 mL)and DCM (30 mL). A catalytic amount of TPAP (35 mg) was added. Theresulting reaction mixture was stirred at RT for 1 hour and evaporatedto dryness. The title aldehyde compound was purified by MPLC using 0-10%ethyl acetate in hexane.

¹H NMR (300 MHz, CD₃OD) δ ppm 1.98-2.10 (m, 1H) 2.12-2.28 (m, 7H)2.80-2.90 (m, 2H) 3.08-3.18 (m, 1H) 3.76-3.85 (m, 1H) 3.90-3.98 (m, 1H)6.75-6.82 (m, 2H) 6.88-6.95 (m, 3H) 7.05-7.25 (m, 4H) 7.80 (d, J=8.79Hz, 2H) 9.79 (s, 1H).

Intermediates 2 through 6 were prepared according to the proceduredescribed in Example 1 from the corresponding alcohol. The results forintermediates 2 and 3 are tabulated below in Table 1.

TABLE 1 Interm. No. IUPAC name ¹H NMR δ (ppm) 2

¹H NMR (600 MHz, CD₃OD) δ ppm 1.59-1.66 (m, 2 H) 1.70-1.82 (m, 1 H)1.82- 1.94 (m, 1 H) 2.14 (s, 3 H) 2.16 (s, 3 H) 2.70-2.96 (m, 3 H) 3.97(t, J = 6.31 Hz, 2 H) 6.73 (d, J = 7.63 Hz, 1 H) 6.79 (s, 1 H) 6.91 (d,J = 7.63 Hz, 1 H) 6.94-7.00 (m, 2 H) 7.07 (d, J = 7.34 Hz, 1 H) 7.11-7.17 (m, 2 H) 7.19-7.29 (m, 1 H) 7.82 (d, J = 8.51 Hz, 2 H) 9.81 (s, 1H) 3

¹H NMR (300 MHz, CD₃OD) δ ppm 1.25-1.39 (m, 2 H) 1.55-1.88 (m, 4 H) 2.14(s, 3 H) 2.15 (s, 3 H) 2.69-2.91 (m, 3 H) 3.94 (t, J = 6.45, 2 H)6.62-6.82 (m, 2 H) 6.84- 7.07 (m, 4 H) 7.08-7.21 (m, 3 H) 7.81 (d, J =8.87 Hz, 2 H) 9.80 (s, 1 H) 4

¹H NMR (300 MHz, CDCl₃) δ ppm 1.60-1.74 (m, 2 H) 1.75-1.97 (m, 2 H) 2.19(d, J = 3.22 Hz, 6 H) 2.72-2.91 (m, 2 H) 3.20-3.39 (m, 1 H) 3.94 (t, J =6.30 Hz, 2 H) 6.61- 6.70 (m, 1 H) 6.72-6.82 (m, 1 H) 6.85 (br. s, 1 H)6.87-7.03 (m, 5 H) 7.80 (d, J = 7.81 Hz, 2 H) 9.87 (s, 1 H) 5

¹H NMR (300 MHz, CDCl₃) δ ppm 1.57-1.78 (m, 3 H) 1.78-1.93 (m, 1 H) 2.19(s, 3 H) 2.20 (s, 3 H) 2.82 (t, J = 8.06 Hz, 2 H) 2.93-3.07 (m, 1 H)3.80-3.98 (m, 2 H) 6.76 (d, J = 7.33 Hz, 1 H) 6.81 (br. s, 1 H)6.84-7.02 (m, 5 H) 7.26 (dd, J = 4.98, 2.93 Hz, 1 H) 7.80 (d, J = 7.80Hz, 2 H) 9.86 (s, 1 H) 6

¹H NMR (600 MHz, CD₃OD) δ ppm 1.58-1.70 (m, 2 H) 1.72-1.82 (m, 1 H)1.85- 1.95 (m, 1 H) 2.16 (s, 3 H) 2.17 (s, 3 H) 3.72-3.78 (m, 1 H)3.82-3.88 (m, 1 H) 3.90- 3.98 (m, 1 H) 4.10 (t, J = 6.15 Hz, 2 H)6.65-6.82 (m, 5 H) 6.92 (d, J = 7.70 Hz, 1 H) 7.00 (d, J = 8.50 Hz, 2 H)7.83 (d, J = 8.50 Hz, 2 H) 9.81 (s, 1 H) 7

¹H NMR (300 MHz, CDCl₃) δ ppm 1.54-1.77 (m, 3 H) 1.78-1.98 (m, 1 H) 2.19(br s, 6 H) 2.68-2.92 (m, 3 H) 3.93 (t, J = 5.86 Hz, 2 H) 6.56- 6.76 (m,1 H) 6.75-6.86 (m, 2 H) 6.85-7.12 (m, 5 H) 7.80 (d, J = 8.20 Hz, 2 H)9.87 (s, 1 H)

EXAMPLE 2 Compound 11-(4-{([4-(2,3-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)azetidine-3-carboxylicacid

A mixture of Intermediate 4 (147 mg, 0.36 mmoles), azetidine carboxylicacid (36.3 mg, 1.0 eq), HOAc (7 drops) and NaCNBH₃ (23.0 mg, 1.0 eq)were reacted as outlined is Scheme 1 to give Compound 1.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.39-1.62 (m, 2H) 1.62-1.92 (m, 2H) 2.09(s, 6H) 2.70-2.95 (m, 2H) 3.04-3.18 (m, 3H) 3.20-3.34 (m, 3H) 3.41 (br.s, 2H) 3.73-3.91 (m, 2H) 6.69-6.79 (m, 3H) 6.81-6.87 (m, 1H) 6.89-6.98(m, 2H) 7.06-7.22 (m, 4H).

Compounds 2 through 7 were prepared according to the procedure describedin Example 2 from the corresponding aldehyde. The starting materials andthe results are tabulated below in Table 2.

TABLE 2 Comp. Interm. No. IUPAC name No. ¹H NMR δ (ppm) 2

1 ¹H NMR (300 MHz, CD₃OD) δ ppm 1.92- 2.04 (m, 1 H) 2.09-2.24 (m, 7 H)2.76-2.95 (m, 2 H) 3.12 (m, 1 H) 3.14- 3.25 (m, 1 H) 3.42 (t, J = 8.66Hz, 2 H) 3.59 (t, J = 8.66 Hz, 2 H) 3.63 (s, 2 H) 3.69 (m, 1 H) 3.82 (m,1 H) 6.70-6.78 (m, 3 H) 6.81 (s, 1 H) 6.92 (d, J = 7.63 Hz, 1 H) 7.02-7.08 (m, 1 H) 7.06-7.25 (m, 5 H) 3

2 ¹H NMR (300 MHz, CD₃OD) δ ppm 1.48-1.66 (m, 2 H) 1.72-1.90 (m, 2 H)2.15 (s, 3 H) 2.17 (s, 3 H) 2.67-2.90 (m, 3 H) 3.20 (quin, J = 8.30 Hz,1 H) 3.45 (t, J = 8.20 Hz, 2 H) 3.54 (t, J = 8.20 Hz, 2 H) 3.59 (s, 2 H)3.85 (t, J = 6.30 Hz, 2 H) 6.63- 6.84 (m, 4 H) 6.91 (d, J = 7.62 Hz, 1H) 7.05 (d, J = 7.62 Hz, 1 H) 7.10- 7.31 (m, 5 H) 4

6 ¹H NMR (300 MHz, CD₃OD) δ ppm 1.51-1.67 (m, 2 H) 1.69-1.94 (m, 2 H)2.16 (s, 3 H) 2.17 (s, 3 H) 2.68-2.97 (m, 3 H) 3.14-3.25 (m, 1 H) 3.42(t, J = 8.06 Hz, 2 H) 3.59 (t, J = 8.06 Hz, 2 H) 3.64 (s, 2 H) 3.87 (t,J = 6.15 Hz, 2 H) 6.63- 6.85 (m, 7 H) 6.92 (d, J = 7.62 Hz, 1 H) 7.18(d, J = 8.49 Hz, 2 H) 5

3 ¹H NMR (600 MHz, CD₃OD) δ ppm 1.29 (quin, J = 7.70 Hz, 2 H) 1.55-1.84(m, 4 H) 2.14 (s, 3 H) 2.16 (s, 3 H) 2.70-2.76 (m, 1 H) 2.78-2.85 (m, 2H) 3.19 (quin, J = 8.36 Hz, 1 H) 3.37 (t, J = 8.66 Hz, 2 H) 3.54 (t, J =8.66 Hz, 2 H) 3.59 (s, 2 H) 3.72-3.88 (m, 2 H) 6.72 (dd, J = 7.63, 1.76Hz, 1 H) 6.73-6.80 (m, 3 H) 6.90 (d, J = 7.63 Hz, 1 H) 7.03 (dt, J =7.56, 1.36 Hz, 1 H) 7.08-7.27 (m, 5 H) 6

5 ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.45- 1.62 (m, 2 H) 1.64- 1.82 (m, 2H) 2.11 (s, 6 H) 2.75 (d, J = 7.33 Hz, 2 H) 3.06-3.18 (m, 3 H) 3.21-3.34(m, 3 H) 3.40 (br. s, 2 H) 3.76- 3.84 (m, 2 H) 6.74 (d, J = 8.50 Hz, 3H) 6.82- 6.86 (m, 1 H) 6.92 (d, J = 7.91 Hz, 1 H) 7.02 (d, J = 4.98 Hz,1 H) 7.06- 7.12 (m, 3 H) 7.41 (dd, J = 4.83, 3.08 Hz, 1 H). 7

7 ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.33- 1.54 (m, 2 H) 1.55- 1.82 (m, 2H) 2.10 (s, 6 H) 2.64-2.82 (m, 2 H) 2.85-2.96 (m, 1 H) 3.11 (br. s., 3H) 3.29 (br. s., 2 H) 3.41 (br. s, 2 H) 3.81 (t, J = 6.01 Hz, 2 H) 6.74(d, J = 8.50 Hz, 3 H) 6.84 (br. s, 1 H) 6.91 (d, J = 7.62 Hz, 1 H)6.95-7.02 (m, 1 H) 7.09 (d, J = 8.50 Hz, 2 H) 7.20-7.33 (m, 2 H)

Biological Data

Compounds were synthesized and tested for S1P1 activity using the GTPγ³⁵S binding assay. These compounds may be assessed for their ability toactivate or block activation of the human S1P1 receptor in cells stablyexpressing the S1P1 receptor. GTP γ³⁵S binding was measured in themedium containing (mM) HEPES 25, pH 7.4, MgCl₂ 10, NaCl 100,dithitothreitol 0.5, digitonin 0.003%, 0.2 nM GTP γ³⁵S, and 5 μgmembrane protein in a volume of 150 μl. Test compounds were included inthe concentration range from 0.08 to 5,000 nM unless indicatedotherwise. Membranes were incubated with 100 μM5′-adenylylimmidodiphosphate for 30 min, and subsequently with 10 μM GDPfor 10 min on ice. Drug solutions and membrane were mixed, and thenreactions were initiated by adding GTP γ³⁵S and continued for 30 min at25° C. Reaction mixtures were filtered over Whatman GF/B filters undervacuum, and washed three times with 3 mL of ice-cold buffer (HEPES 25,pH7.4, MgCl₂ 10 and NaCl 100). Filters were dried and mixed withscintillant, and counted for ³⁵S activity using a β-counter.Agonist-induced GTP γ³⁵S binding was obtained by subtracting that in theabsence of agonist. Binding data were analyzed using a non-linearregression method. In case of antagonist assay, the reaction mixturecontained 10 nM S1P in the presence of test antagonist at concentrationsranging from 0.08 to 5000 nM.

Table 3 shows activity potency: S1P1 receptor from GTP γ³⁵S: nM, (EC₅₀).Activity potency: S1P1 receptor from GTP γ³⁵S: nM, (EC₅₀),

TABLE 3 S1P1 IUPAC name EC₅₀ (nM)1-(4-{[5-(3-chlorophenyl)-6-(3,4-dimethylphenyl) 203.78hexyl]oxy}benzyl) azetidine-3-carboxylic acid1-{4-[3-(3-chlorophenyl)-4-(3,4- 50.18dimethylphenyl)butoxy]benzyl}azetidine-3-carboxylic acid1-(4-{[4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl) 1.4 pentyl]oxy}benzyl)azetidine-3-carboxylic acid1-(4-{[5-(3-chlorophenyl)-6-(3,4-dimethylphenyl) 1.7hexyl]oxy}benzyl)azetidine-3-carboxylic acid1-(4-{[5-(3,4-dimethylphenyl)-4-(3- 5.7thienyl)pentyl]oxy}benzyl)azetidine-3-carboxylic acid1-(4-{[4-(2,3-difluorophenyl)-5-(3,4-dimethylphenyl) 1.37pentyl]oxy}benzyl) azetidine-3-carboxylic acid

What is claimed is:
 1. A compound represented by Formula I, itsenantiomers, diastereoisomers, hydrates, solvates, crystal forms andindividual isomers, tautomers or a pharmaceutically acceptable saltthereof,

wherein: A is optionally substituted C₆₋₁₀ aryl, optionally substitutedheterocycle, optionally substituted C₃₋₈ cycloalkyl or optionallysubstituted C₃₋₈ cycloalkenyl; B is optionally substituted C₆₋₁₀ aryl,optionally substituted heterocycle, optionally substituted C₃₋₈cycloalkyl or optionally substituted C₃₋₈ cycloalkenyl; R¹ is H,halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl, CN, C(O)R¹¹,NR¹²R¹³ or hydroxyl; R² is H, halogen, —OC₁₋₈ alkyl, optionallysubstituted C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R³ is H,halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl, CN, C(O)R¹¹,NR¹²R¹³ or hydroxyl; R⁴ is H, halogen, —OC₁₋₈ alkyl, optionallysubstituted C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R⁵ is H,halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl, CN, C(O)R¹¹,NR¹²R¹³ or hydroxyl; R⁶ is H, halogen, —OC₁₋₈ alkyl, optionallysubstituted C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R⁷ is H,halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl, CN, C(O)R¹¹,optionally substituted C₆₋₁₀ aryl, optionally substituted heterocycle,optionally substituted C₃₋₈ cycloakyl, optionally substituted Ccycloalkenyl, NR¹²R¹³ or hydroxyl; R⁸ is H, halogen, —OC₁₋₈ alkyl,optionally substituted C₁₋₈ alkyl, CN, C(O)R¹¹, optionally substitutedC₆₋₁₀ aryl, optionally substituted heterocycle, optionally substitutedC₃₋₈ cycloakyl, optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ orhydroxyl; R⁹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈alkyl, CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionallysubstituted heterocycle, optionally substituted C₃₋₈ cycloakyl,optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl; R¹⁰ is H,halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl, CN, C(O)R¹¹,C₆₋₁₀ aryl, optionally substituted heterocycle, optionally substituted Ccycloakyl, optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ orhydroxyl; L¹ is O, S, NH or CHR¹²; L² is O, S or CHR¹²; R¹¹ is H, OH orC₁₋₈ alkyl; a is 1, 2, 3, 4, 5 or 6; R¹² is H or C₁₋₈ alkyl; and R¹³ isH or C₁₋₈ alkyl.
 2. A compound according to claim 1 wherein L¹ is CH₂.3. A compound according to claim 1 wherein L² is CH₂.
 4. A compoundaccording to claim 1 wherein a is 1, 2 or
 3. 5. A compound according toclaim 1 wherein


6. A compound according to claim 5, wherein


7. A compound according to claim 5, wherein:


8. A compound according to claim 5, wherein


9. A compound according to claim 1, wherein: R¹ is H or halogen; R² is Hor halogen; R³ is H or halogen; R⁴ is H or halogen; R⁵ is H or C₁₋₈alkyl; and R⁶ is H or C₁₋₈ alkyl.
 10. A compound according to claim 1,selected from:1-(4-{[5-(3-chlorophenyl)-6-(3,4-dimethylphenyl)hexyl]oxy}benzyl)azetidine-3-carboxylicacid;1-{4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}azetidine-3-carboxylicacid;1-(4-{[4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)azetidine-3-carboxylicacid;1-(4-{[4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)azetidine-3-carboxylicacid;1-(4-{[4-(3,4-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)azetidine-3-carboxylicacid;1-(4-{[5-(3,4-dimethylphenyl)-4-(3-thienyl)pentyl]oxy}benzyl)azetidine-3-carboxylicacid; and1-(4-{[4-(2,3-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)azetidine-3-carboxylicacid.
 11. A pharmaceutical composition comprising as active ingredient atherapeutically effective amount of a compound according to claim 1 anda pharmaceutically acceptable adjuvant, diluent or carrier.
 12. Apharmaceutical composition according to claim 11 wherein the compound isselected from:1-(4-{[5-(3-chlorophenyl)-6-(3,4-dimethylphenyl)hexyl]oxy}benzyl)azetidine-3-carboxylicacid;1-{4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}azetidine-3-carboxylicacid;1-(4-{[4-(3,5-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)azetidine-3-carboxylicacid;1-(4-{[4-(3-chlorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)azetidine-3-carboxylicacid;1-(4-{[4-(3,4-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)azetidine-3-carboxylicacid;1-(4-{[5-(3,4-dimethylphenyl)-4-(3-thienyl)pentyl]oxy}benzyl)azetidine-3-carboxylicacid; and1-(4-{[4-(2,3-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}benzyl)azetidine-3-carboxylicacid.
 13. A method of treating a disorder associated withsphingosine-1-phosphate receptor modulation, which comprisesadministering to a mammal in need thereof, a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundof Formula I

wherein: A is optionally substituted C₆₋₁₀ aryl, optionally substitutedheterocycle, optionally substituted C₃₋₈ cycloalkyl or optionallysubstituted C₃₋₈ cycloalkenyl; B is optionally substituted C₆₋₁₀ aryl,optionally substituted heterocycle, optionally substituted C₃₋₈cycloalkyl or optionally substituted C₃₋₈ cycloalkenyl; R¹ is H,halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl, CN, C(O)R¹¹,NR¹²R¹³ or hydroxyl; R² is H, halogen, —OC₁₋₈ alkyl, optionallysubstituted C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R³ is H,halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl, CN, C(O)R¹¹,NR¹²R¹³ or hydroxyl; R⁴ is H, halogen, —OC₁₋₈ alkyl, optionallysubstituted C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R⁵ is H,halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl, CN, C(O)R¹¹,NR¹²R¹³ or hydroxyl; R⁶ is H, halogen, —OC₁₋₈ alkyl, optionallysubstituted C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R⁷ is H,halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl, CN, C(O)R¹¹,optionally substituted C₆₋₁₀ aryl, optionally substituted heterocycle,optionally substituted C₃₋₈ cycloakyl, optionally substituted C₃₋₈cycloalkenyl, NR¹²R¹³ or hydroxyl; R⁸ is H, halogen, —OC₁₋₈ alkyl,optionally substituted C₁₋₈ alkyl, CN, C(O)R¹¹, optionally substitutedC₆₋₁₀ aryl, optionally substituted heterocycle, optionally substitutedC₃₋₈ cycloakyl, optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ orhydroxyl; R⁹ is H, halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈alkyl, CN, C(O)R¹¹, optionally substituted C₆₋₁₀ aryl, optionallysubstituted heterocycle, optionally substituted C₃₋₈ cycloakyl,optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl; R¹⁰ is H,halogen, —OC₁₋₈ alkyl, optionally substituted C₁₋₈ alkyl, CN, C(O)R¹¹,C₆₋₁₀ aryl, optionally substituted heterocycle, optionally substitutedC₃₋₈ cycloakyl, optionally substituted C₃₋₈ cycloalkenyl, NR¹²R¹³ orhydroxyl; L¹ is O, S, NH or CHR¹²; L² is O, S or CHR¹²; R¹¹ is H, OH orC₁₋₈ alkyl; a is 1, 2, 3, 4, 5 or 6; R¹² is H or C₁₋₈ alkyl; and R¹³ isH or C₁₋₈ alkyl.
 14. A method of claim 13, wherein the pharmaceuticalcomposition is administered to the mammal to treat ocular disease, wetand dry age-related macular degeneration, diabetic retinopathy,retinopathy of prematurity, retinal edema, geographic atrophy,glaucomatous optic neuropathy, chorioretinopathy, hypertensiveretinopathy, dry eye, ocular ischemic syndrome, prevention ofinflammation-induced fibrosis in the back of the eye, various ocularinflammatory diseases including uveitis, scleritis, keratitis, andretinal vasculitis; or systemic vascular barrier related diseases ,various inflammatory diseases, including acute lung injury, itsprevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas,and ventilation-induced lung injury; or autoimmune diseases andimmunosuppression , rheumatoid arthritis, Crohn's disease, Graves'disease, inflammatory bowel disease, multiple sclerosis, Myastheniagravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renalischemia/perfusion injury, contact hypersensitivity, atopic dermatitis,and organ transplantation; or allergies and other inflammatory diseases, urticaria, bronchial asthma, and other airway inflammations includingpulmonary emphysema and chronic obstructive pulmonary diseases; orcardiac protection , ischemia reperfusion injury and atherosclerosis; orwound healing, scar-free healing of wounds from cosmetic skin surgery,ocular surgery, GI surgery, general surgery, oral injuries, variousmechanical, heat and burn injuries, prevention and treatment ofphotoaging and skin ageing, and prevention of radiation-inducedinjuries; or bone formation, treatment of osteoporosis and various bonefractures including hip and ankles; or anti-nociceptive activity ,visceral pain, pain associated with diabetic neuropathy, rheumatoidarthritis, chronic knee and joint pain, tendonitis, osteoarthritis,neuropathic pains.
 15. The method of claim 13 wherein the mammal is ahuman.